C-C Chemokine Receptor Type 2-Targeting Ultrasmall Copper Nanoparticles for Positron Emission Tomography-Guided Delivery of Gemcitabine for Pancreatic Ductal Adenocarcinoma

1469 Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with dire prognosis due to aggressive biology, lack of effective tools for early detection, and limited treatment options. The C-C motif chemokine 2 (CCL2) and its cognate receptor CCR2 (CCL2/CCR2) axis is critical in fostering and maintaining the PDAC stroma rich tumor microenvironment by recruiting immunosuppressive myeloid cells. Herein, we engineered CCR2-targeting ultrasmall copper nanoclusters (CuNCs) as nano-vehicles not only for targeted PET imaging by intrinsic radiolabeling with 64Cu but also for loading and delivery of chemotherapy drug gemcitabine to PDAC. Methods: The CCR2 targeting peptide ECL1i and gemcitabine were covalently conjugated on the nanoparticles to produce the targeting (CuNCs-ECL1i) and drug loaded (CuNCs-ECL1i-Gem) nanoclusters, respectively. Biodistribution of both nanoclusters was performed in wildtype mice . PET/CT imaging using 64Cu-CuNCs-ECL1i was measured in two genetically-engineered mouse models (GEMMs) including p48-CRE; LSL-KRasG12D/wt; p53flox/flox (KPPC) and p48-CRE; LSL-KrasG12D/wt; p53flox/wt (KPC) mice. CuNCs-ECL1i-Gem treatment efficacy was evaluated using a syngeneic KI xenografts. The in vivo CuNC toxicity was also assessed. Results: The CCR2 targeting and drug loading nanoclusters were obtained with high yield and radiolabeling specific activity. Biodistribution demonstrated similar pharmacokinetics between 64Cu-CuNCs-ECL1i and 64Cu-CuNCs-ECL1i-Gem. In both KPPC and KPC mice, 64Cu-CuNCs-ECL1i showed tumor uptake of 11.16 ± 1.22 %ID/g (n=5) and 5.47 ± 0.75 %ID/g (n=5), respectively, which were significantly higher than the tracer accumulation in pancreases of control littermates and the data obtained with non-targeting nanoclusters in tumor-bearing mice. Systemic administration of CuNCs-ECL1i-Gem significantly inhibited the growth of PDAC tumors in the KI xenograft mouse model and prolonged survival. Moreover, the in vivo CuNC toxicity assessment demonstrated the safety of our current treatment regimen. Conclusions: A CCR2-targeting ultrasmall nanocluster for PDAC imaging and therapy were developed. The sensitive and specific tumor targeting in GEMMs and effective tumor inhibition in PDAC xenograft model demonstrated its potential for PDAC imaging guided therapy and warranted further investigation for future translation. Research support: P50CA196510, R01CA235672, ECS-0335765.